Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low-Density Lipoprotein Cholesterol

Abstract

Background: Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid-related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations.

Methods and results: We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo-allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non-high-density lipoprotein cholesterol, and triglycerides, but not LDL-c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On-statin levels of the smallest VLDL particle subclass were associated with a 68% per-SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk-this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C-index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein-related risk were observed.

Conclusions: Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: atherosclerosis; lipids and lipoproteins; metabolomics; nuclear magnetic resonance spectroscopy; prevention.

Figure 1

Overview of the study: impetus for the study, study populations, lipoprotein measures, lipoprotein profiling, and results. CATHGEN indicates CATHeterization GENetics biorepository; CVD, cardiovascular disease; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; LDL, low‐density lipoproteins; LDL‐c, low‐density lipoprotein cholesterol; NMR, nuclear magnetic resonance spectroscopy; VLDL, very low‐density lipoproteins.

Figure 2

Schematic representation of the median proportion of atherogenic (LDL and VLDL) lipoprotein subclasses (median subclass particle concentration divided by median total LDL+VLDL particle concentration measured with NMR) at baseline in fasting samples in the rosuvastatin arm pre‐treatment. IDL‐p indicates intermediate density lipoprotein particle concentration; LDL‐p, low density lipoprotein particle concentration; NMR, nuclear magnetic resonance; VLDL‐p, very low density lipoprotein particle concentration.

Figure 3

Adjusted* HR and 95%CI for the primary incident CVD end point in the JUPITER placebo group associated with baseline marker levels. ApoB indicates apolipoprotein B; CM, chylomicrons; HR, hazard ratio; IDL‐p, intermediate density lipoprotein particle concentration; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial; LDL‐c, low‐density lipoprotein cholesterol; LDL‐p, low‐density lipoprotein particle concentration; non‐HDL‐c, non‐high‐density lipoprotein cholesterol concentration; RC, calculated remnant cholesterol; TG, triglycerides; VLDL‐c, very low‐density lipoprotein cholesterol; VLDL‐p, very low‐density lipoprotein particle concentration. *Adjusted for age, sex, race, smoking status, family history of premature coronary disease, body‐mass index, systolic blood pressure, fasting glucose, and hsCRP. ^† LDL size was no longer associated with either end point after adjusting for LDL‐p and HDL‐c. The following biomarkers were natural‐log‐transformed: triglyceride, RC, small LDL‐p, IDL‐p, all VLDL‐p subclasses, VLDL/CM triglycerides, and VLDL‐c.

Figure 4

Median percentage change in lipids, apoB, and NMR‐measured lipoprotein subclasses in the placebo and statin‐treated arms in JUPITER. Error bars represent 25th and 75th percentiles. CM indicates chylomicrons; IDL‐p, intermediate‐density lipoprotein particle concentration; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial; LDL‐c, low‐density lipoprotein cholesterol; LDL‐p, low‐density lipoprotein particle concentration; NMR, nuclear magnetic resonance; non‐HDL‐c, non‐high‐density lipoprotein cholesterol concentration; RC, calculated remnant cholesterol; TG, triglycerides; VLDL‐c, very low‐density lipoprotein cholesterol; VLDL‐p, very low density lipoprotein particle concentration.

Figure 5

On‐statin adjusted* HR and 95%CI for the primary incident CVD end point in the JUPITER rosuvastatin 20‐mg group. CM indicates chylomicrons; HR, hazard ratio; IDL‐p, intermediate‐density lipoprotein particle concentration; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial; LDL‐c, low‐density lipoprotein cholesterol; LDL‐p, low‐density lipoprotein particle concentration; non‐HDL‐c, non‐high‐density lipoprotein cholesterol concentration; RC, calculated remnant cholesterol; SD, standard deviation; TG, triglycerides; VLDL‐c, very low‐density lipoprotein cholesterol; VLDL‐p, very low‐density lipoprotein particle concentration. *Adjusted for age, sex, race, smoking status, family history of premature coronary disease, body‐mass index, systolic blood pressure, fasting glucose, and hsCRP. The following biomarkers were natural‐log‐transformed: triglyceride, RC, small LDL‐p, IDL‐p, all VLDL‐p subclasses, VLDL/CM triglycerides, and VLDL‐c.